The Neuron-Restrictive Silencer Factor (NRSF) is a transcriptional repressor that recognizes the Neuron-Restrictive Silencer Element (NRSE) found in the promoter of several neuron specific genes. Accordingly, NRSF is expressed in most if not all non-neuronal tissues; in developing embryos, the initial expression of NRSF in neuronal progenitors is down- regulated with further differentiation. Such coordinated regulation of NRSF suggests that it plays an important role in the signaling pathway of neuronal proliferation and differentiation. This proposal describes experiments aimed at understanding the role of NRSF in neurogenesis. The main approach will be to disrupt the normal function and expression of NRSF. Ectopic expression of various NRSF derivatives including a dominant negative form will be achieved in several in vitro and in vivo systems. The consequence of the ectopic expression of NRSF derivatives will be assessed in terms of their effect on neuronal differentiation and proliferation. These experiments not only will further our understanding of the role of NRSF in neurogenesis but also may provide insight into the mechanism by which proliferative and differentiative signals are transmitted through transcriptional repressors. As such, the information obtained from the experiments will be relevant to other areas of biology such as cancer biology.